Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells.

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Yee KW, Schittenhelm M, O'Farrell AM, Town AR, McGreevey L, Bainbridge T, Cherrington JM, Heinrich MC

Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells.

Blood. 2004 Dec 15;104(13):4202-9. Epub 2004 Aug 10.

PubMed ID

15304385 [ View in PubMed

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Abstract

Fetal liver tyrosine kinase 3 internal tandem duplication (FLT3 ITD) mutations are the most common molecular abnormality associated with adult acute myeloid leukemia (AML). To exploit this molecular target, a number of potent and specific FLT3 kinase inhibitors have been developed and are currently being tested in early phase clinical trials of patients with refractory AML. To explore the efficacy of combining a FLT3 inhibitor with standard AML chemotherapy drugs, we tested the effect of combining the FLT3 inhibitor SU11248 with cytarabine or daunorubicin on the proliferation and survival of cell lines expressing either mutant (FLT3 ITD or FLT3 D835V) or wild-type (WT) FLT3. SU11248 had additive-to-synergistic inhibitory effects on FLT3-dependent leukemic cell proliferation when combined with cytarabine or daunorubicin. The synergistic interaction of SU11248 and the traditional antileukemic agents was more pronounced for induction of apoptosis. SU11248 inhibited the proliferation of primary AML myeloblasts expressing mutant FLT3 ITD but not WT FLT3 protein. Combining SU11248 and cytarabine synergistically inhibited the proliferation of primary AML myeloblasts expressing FLT3 ITD but not WT FLT3 protein. These data suggest that the addition of potent FLT3 inhibitors such as SU11248 to AML chemotherapy regimens could result in improved treatment results.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Sunitinib	Receptor-type tyrosine-protein kinase FLT3	Protein	Humans	Yes	Inhibitor	Details